The history of inhaled anesthetics dates back for more than a century and a half and was initiated with the use of diethyl ether, chloroform or nitrous oxide in the 1840's. While nitrous oxide is still used in some procedures, today's practitioners generally employ one of three fluorinated ethers—isoflurane of the formula CHF2—O—CHClCF3; desflurane of the formula CHF2—O—CHFCF3 which differs from isoflurane by replacement of the one chloro substituent with a fluoro, and sevoflurane of the formula CH2F—O—CH(CF3)2. In general, the replacement of a chloro substituent with fluoro reduces the solubility of the anesthetic in blood (and thus accelerates recovery from anesthesia) and reduces toxicity. However, other disadvantages associated with desflurane as compared to isoflurane (decreased potency; greater cost of synthesis; greater pungency) somewhat mitigate the advantages of these properties. Sevoflurane also has minimal toxicity and the advantage of absent pungency, but it is significantly more soluble than desflurane and thus is associated with a slower recovery.
These anesthetics result from fairly recent efforts. During the decades of the 60's and 70's, Dr. Ross C. Terrell and his associates at Ohio Medical Products (now Baxter Healthcare Corp.) synthesized over 700 fluorinated compounds in a program for discovery of improved anesthetics. Isoflurane, desflurane and sevoflurane resulted from this effort. Wallin and co-workers at Travenol Laboratories in a similar program provided compounds that also resulted in the synthesis of sevoflurane.
An ideal anesthetic would have anesthetic properties at low concentrations in the lung, have low solubility in the blood, lack pungency, and would have minimal or no toxic or side effects such as enhancing blood pressure. Each of the commonly used inhaled anesthetics described above has a unique spectrum of properties that fall short of the ideal. The properties are described in Eger, II, E. I., et al., “The Pharmacology of Inhaled Anesthetics” (2002) published by Dannemiller Memorial Educational Foundation and incorporated herein by reference.
In standard procedures for administering inhaled fluorocarbon-based anesthetics, it is necessary, for economic reasons, to recycle the inhalant. Because the inhaled anesthetics in current use are difficult to synthesize, they are so expensive that simply administering them to a subject without recovering the exhaled gases from the subject and recycling them would be prohibitively expensive. Thus, a typical procedure for anesthesia by inhalation is shown in FIG. 1.
As shown, the delivered gas enters the cycling system and is transferred to a subject through a valve permitting inhalation. The exhaled gases from the subject are cycled through an expiratory valve to a carbon dioxide absorber which then cleanses the gases of carbon dioxide, permitting the unused previously-inhaled anesthetic to be recycled and again inhaled by the subject.
Traditionally, the carbon dioxide absorber has been a combination of hydroxides, including NaOH, KOH, Ba(OH)2 and Ca(OH)2. In most cases, 80% or more of the absorbent is Ca(OH)2, but KOH and/or NaOH are generally added to accelerate the reaction with carbon dioxide. Further, the absorbent generally contains about 15% of water. The presence of water limits (e.g., sevoflurane) or prevents (e.g., desflurane, isoflurane) degradation to various toxic materials. However, desiccation of absorbents with monovalent bases removes this protection. For example, desiccation of soda lime results in a lime that interacts with desflurane and isoflurane to produce carbon monoxide. However, absorbents that contain only Ca(OH)2 as the base may not have this effect. Murray, J. M., et al., Anesthesiology (1999) 91:1342-1348.
The invention concerns a particular analog of the above-mentioned anesthetics which is of the formula CHF2—O—CH(CF3)2. This compound was included in a series of compounds reported by the Terrell group in an article by Speers, L., et al., J. Med. Chem. (1971) 14:593-595. According to this article, this compound is a good anesthetic although it appeared to have undesirable side effects in murine models. No report of the solubility of this compound appears in the Speers paper.